Semi-starvation induced hyperactivity (SIH) occurs in rodents upon caloric restriction. We hypothesized that SIH is triggered by the decline in leptin secretion associated with food restriction. To test this hypothesis, rats, which had established a stable level of activity, were treated with leptin or vehicle via implanted minipumps concomitantly to initiation of food restriction for 7 days. In a second experiment treatment was initiated after SIH had already set in. In contrast to the vehicle-treated rats, which increased their baseline activity level by 300%, the development of SIH was suppressed by leptin. Furthermore, leptin was able to stop SIH, after it had set in. These results underscore the assumed major role of leptin in the adaptation to semi-starvation. Because SIH has been viewed as a model for anorexia nervosa, we also assessed subjective ratings of motor restlessness in 30 patients with this eating disorder in the emaciated state associated with hypoleptinemia and after increments in leptin secretion brought upon by therapeutically induced weight gain. Hypoleptinemic patients ranked their motor restlessness higher than upon attainment of their maximal leptin level during inpatient treatment. Thus, hypoleptinemia might also contribute to the hyperactivity frequently associated with anorexia nervosa. Molecular Psychiatry (2000) 5, 476-481.Keywords: food intake; food restriction; energy metabolism; neuroendocrine control of appetite; locomotor activity; running wheels Hyperactivity is observed in 40-80% of patients with anorexia nervosa (AN). 1,2 Caloric deprivation severe enough to result in significant weight loss possibly provokes sensations of behavioral arousal and activation in individuals with an innate vulnerability to develop AN. 3 Indeed, reduced food intake and enhanced activity have been viewed as the core symptomatology in AN, because only these behavioral measures consistently distinguish AN from other disorders. 4 Semi-starvation induced hyperactivity (SIH) is a well characterized phenomenon in laboratory animals. 5,6 Rats supplied with food for only 1 h per day manage to survive, but die within a short period of time when exposed to a running wheel. The enhancement of activity is related to the severity of food restriction; total food deprivation results in a disruption of the nocturnal activity pattern. 6 Leptin is assumed to be the major hormone underlying the regulatory phenomena that lead to an adaptation of an organism to reduced energy supplies. 7 Thus, in mice exogenously applied leptin has been shown to blunt the semi-starvation-induced downregulation of the hypothalamic-pituitary gonadal and thyroid axes as well as the upregulation of the hypothalamic-pituitary adrenal axis. 7 The rapid decline in leptin secretion associated with caloric restriction and weight loss 7,8 could represent the initial trigger underlying the hyperactivity observed in SIH and AN. As an initial step towards testing this hypothesis we investigated the effect of continuous leptin treatment via minipum...